(19g) Mechanical Regulation of Cancer Cell Angiogenic Activity

It is now well established that angiogenesis, i.e. formation of blood capillaries, is a requisite not only for tumors to grow beyond 1-2 mm³ and meet their insatiable metabolic demands, but also to act as conduits for cancer cells to reach distant organs and form metastatic lesions. Even though angiogenesis inhibitors have demonstrated potent anti-angiogenic activity in pre-clinical tumor models, clinical responses and survival benefit have been moderate. Limited clinical efficacy may stem from the fact that most clinically available anti-angiogenic agents primarily target vascular endothelial growth factor (VEGF). Tumors overcome VEGF-targeted therapy by producing several other potent angiogenic molecules to induce vascularization. Additionally, crosstalk and compensatory signaling may trigger resistance to anti-VEGF drugs. Deficiencies of current anti-angiogenic drugs highlight the need to identify new therapies that can either act alone or synergistically to suppress tumor vascularization. While chemical signaling molecules involved in neovascularization have been defined, designing and developing effective anti-angiogenic therapies requires identifying and targeting signaling hubs that drive the “angiogenic switch” of cancer cells. This study examined the influence of matrix stiffening on angiogenic activity of breast cancer cells.

Non-enzymatic glycation of collagen with different concentrations ribose was carried out to engineer mechanically tunable (same protein concentration) matrices. Highly invasive (MDA-MB-231) and non-invasive (MCF-7) breast cancer cells were encapsulated in these matrices of varying mechanics and cultured in the presence of serum-free media. 4 days post-fabrication, the spent media (containing secreted bioactive factors) were collected and concentrations of angiogenic molecules in the media were measured via Proteome Profiler^TM Human Angiogenesis Array (R&D Systems). Matrix stiffening altered angiogenic activity of MDA-MB-231 cells as manifested from enhanced secretion of pro-angiogenic (e.g. VEGF and angiopoentin-2) and reduced secretion of anti-angiogenic factors (e.g. TIMP-1 and thrombospondin-2). However, such drastic effects were not observed for MCF-7 cells indicating less dependency on matrix stiffness. These data suggest the existence of a potential mechanoregulatory circuit in controlling tumor vascularization. The impact of inhibiting mechanotransduction events on angiogenic activity of cancer cells will be discussed.

This study was supported by Alternatives Research and Development Foundation.